Contrasting effects of selective MAGL and FAAH inhibition on dopamine depletion and GDNF expression in a chronic MPTP mouse model of Parkinson's disease

Pasquarelli, Noemi; Porazik, Christoph; Bayer, Hanna; Buck, Eva; Schildknecht, Stefan; Weydt, Patrick; Witting, Anke; Ferger, Boris

doi:10.1016/j.neuint.2017.08.003

Cited by 39 publications

(36 citation statements)

References 79 publications

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“…MAGL may be particularly related to cortical thinning through its regulation of 2-AG, which has a greater involvement in synaptic plasticity than FAAHregulated anandamide [69,70]. Further, MAGL inhibitors increased glial-derived neurotrophic factors and prevented neurodegeneration in a mouse model of Parkinson's disease, but FAAH inhibition did not [71]. These data, together with the predominance of 2-AG in cortex relative to anandamide, suggest that MAGL may be an important target for understanding cortical thinning in CD.…”

Section: Cortical Thickness Differences In Cd: Association With Magl mentioning

confidence: 99%

Brain structural changes in cannabis dependence: association with MAGL

et al. 2019

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Cannabis use is rising, yet there is poor understanding of biological processes that might link chronic cannabis use to brain structural abnormalities. To lend insight into this topic, we examined white matter microstructural integrity and gray matter cortical thickness/density differences between 89 individuals with cannabis dependence (CD) and 89 matched controls (64 males, 25 females in each group) from the Human Connectome Project. We tested whether cortical patterns for expression of genes relevant for cannabinoid signaling (from Allen Human Brain Atlas postmortem tissue) were associated with spatial patterns of cortical thickness/density differences in CD. CD had lower fractional anisotropy than controls in white matter bundles innervating posterior cingulate and parietal cortex, basal ganglia, and temporal cortex. The CD group also had significantly less gray matter thickness and density in precuneus, relative to controls. Sibling-pair analysis found support for causal and graded liability effects of cannabis on precuneus structure. Spatial patterns of gray matter differences in CD were significantly associated with regional differences in monoacylglycerol lipase (MAGL) expression in postmortem brain tissue, such that regions with higher MAGL expression (but not fatty-acid amide hydrolase or FAAH) were more vulnerable to cortical thinning. In sum, chronic cannabis use is associated with structural differences in white and gray matter, which was most prominent in precuneus and associated white matter tracts. Regions with high MAGL expression, and therefore with potentially physiologically restricted endogenous cannabinoid signaling, may be more vulnerable to the effects of chronic cannabis use on cortical thickness.

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Section: Cortical Thickness Differences In Cd: Association With Magl mentioning

confidence: 99%

Brain structural changes in cannabis dependence: association with MAGL

et al. 2019

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“…These differential effects could be associated with the different mechanisms leading to the degeneration of these brain areas; in PD patients, the SN presents with cell loss [187], while the putamen has DA depletion [188]. In PD models, pharmacological inhibition of MAG lipase has neuroprotective effects in both SH-SY5Y cells treated with MPP+ [189] and chronic MPTP/probenecid mouse models [190,191]. Although there is no information on the levels of MAG in PD patients, the model studies suggest that MAG lipase inhibition, and thus higher levels of MAG, may be protective for PD.…”

Section: Glycerolipidsmentioning

confidence: 99%

The Role of Lipids in Parkinson’s Disease

Xicoy

Wieringa

Martens

2019

Cells

189

161

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Parkinson’s disease (PD) is a neurodegenerative disease characterized by a progressive loss of dopaminergic neurons from the nigrostriatal pathway, formation of Lewy bodies, and microgliosis. During the past decades multiple cellular pathways have been associated with PD pathology (i.e., oxidative stress, endosomal-lysosomal dysfunction, endoplasmic reticulum stress, and immune response), yet disease-modifying treatments are not available. We have recently used genetic data from familial and sporadic cases in an unbiased approach to build a molecular landscape for PD, revealing lipids as central players in this disease. Here we extensively review the current knowledge concerning the involvement of various subclasses of fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, sterols, and lipoproteins in PD pathogenesis. Our review corroborates a central role for most lipid classes, but the available information is fragmented, not always reproducible, and sometimes differs by sex, age or PD etiology of the patients. This hinders drawing firm conclusions about causal or associative effects of dietary lipids or defects in specific steps of lipid metabolism in PD. Future technological advances in lipidomics and additional systematic studies on lipid species from PD patient material may improve this situation and lead to a better appreciation of the significance of lipids for this devastating disease.

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“…While PF-3845 did not show some degree of protection, it reduced CB2 expression. Thus, MAGL inhibition is a better choice for PD treatment [ 106 ].…”

Section: Faah/magl Inhibitor Application As a New Strategy For Futurementioning

confidence: 99%

Potential application of endocannabinoid system agents in neuropsychiatric and neurodegenerative diseases—focusing on FAAH/MAGL inhibitors

et al. 2020

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The endocannabinoid system (ECS) has received extensive attention for its neuroprotective effect on the brain. This system comprises endocannabinoids, endocannabinoid receptors, and the corresponding ligands and proteins. The molecular players involved in their regulation and metabolism are potential therapeutic targets for neuropsychiatric diseases including anxiety, depression and neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). The inhibitors of two endocannabinoid hydrolases, i.e., fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), have the capacity to increase the level of endocannabinoids indirectly, causing fewer side effects than those associated with direct supplementation of cannabinoids. Their antidepressant and anxiolytic mechanisms are considered to modulate the hypothalamic-pituitary-adrenal axis and regulate synaptic and neural plasticity. In terms of AD/PD, treatment with FAAH/MAGL inhibitors leads to reduction in amyloid β-protein deposition and inhibition of the death of dopamine neurons, which are commonly accepted to underlie the pathogenesis of AD and PD, respectively. Inflammation as the cause of depression/anxiety and PD/AD is also the target of FAAH/MAGL inhibitors. In this review, we summarize the application and involvement of FAAH/MAGL inhibitors in related neurological diseases. Focus on the latest research progress using FAAH/MAGL inhibitors is expected to facilitate the development of novel approaches with therapeutic potential.

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Contrasting effects of selective MAGL and FAAH inhibition on dopamine depletion and GDNF expression in a chronic MPTP mouse model of Parkinson's disease

Cited by 39 publications

References 79 publications

Brain structural changes in cannabis dependence: association with MAGL

Brain structural changes in cannabis dependence: association with MAGL

The Role of Lipids in Parkinson’s Disease

Potential application of endocannabinoid system agents in neuropsychiatric and neurodegenerative diseases—focusing on FAAH/MAGL inhibitors

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